Design of Delivery Vehicle Based On Rolling Model

Abstract

Objects of the present invention are to provide a method for designing an optimum delivery preparation with the use of a convenient experiment and/or assay and to search for the thus produced delivery vehicle. The present invention provides a method for producing a delivery vehicle for achieving the delivery of a desired substance to a desired site, which comprises the steps of: A) measuring in vitro affinity of candidate delivery vehicles for a cell surface molecule such as a lectin associated with the site; and B) selecting a delivery vehicle having in vitro affinity corresponding to delivery to the desired site.

1 .- 111 . (canceled) 
   
   
       112 . A delivery vehicle for achieving delivery to a desired site in which a strong binding IC involved in in vitro affinity for a cell surface molecule associated with the desired site is low and a weak binding IC involved in in vitro affinity for the same is high, and the cell surface molecule is selected from the group consisting of a lectin, an adhesion molecule, an integrin, an immunoglobulin, a sialomucin, a cadherin, a protein, a lipid, a receptor, an antigen, an enzyme, a metalloprotease, a tyrosine phosphatase, a glycolipid, a glycoprotein, a proteoglycan, a costimuratory molecule, a membrane protein, and an extracellular matrix. 
   
   
       113 . The delivery vehicle according to  claim 112 , in which the delivery vehicle is a liposome, and the boundary between the strong binding IC and the weak binding IC is between 30 and 31 for “n” of ICn. 
   
   
       114 . The delivery vehicle according to  claim 113 , in which the delivery vehicle is a sugar-chain-modified liposome. 
   
   
       115 . The delivery vehicle according to  claim 112 , in which the desired site is selected from the group consisting of an inflammation site and a cancer site. 
   
   
       116 . The delivery vehicle according to  claim 112 , in which an inhibitory concentration at a strong binding IC which is approximately IC30 or less is 10 −9 M or less and an inhibitory concentration at a weak binding IC which is approximately IC31 or more is 10 −9 M or more as to in vitro affinity for a lectin associated with a desired state. 
   
   
       117 . The delivery vehicle according to  claim 112 , which satisfies at least one condition selected from the group consisting of a condition that the inhibitory concentration at IC 10 is 10 −9 M or less, a condition that an inhibitory concentration at IC20 is 10 −9 M or less and a condition that an inhibitory concentration at IC30 is 10 −9 M or less for the strong binding IC as to in vitro affinity for a lectin associated with a desired site, and satisfies at least one condition selected from the group consisting of a condition that the inhibitory concentration at IC40 is 10 −9 M or more, a condition that the inhibitory condition of IC50 is 10 −9 M or more and a condition that the inhibitory concentration at IC60 is 10 −9 M or more for the weak binding IC as to in vitro affinity for a lectin associated with a desired site. 
   
   
       118 . The delivery vehicle according to  claim 112 , in which the IC is measured based on affinity for E-selectin. 
   
   
       119 . The delivery vehicle according to  claim 116 , which contains a liposome selected from the group consisting of liposome No. 16, liposome No. 27, liposome No. 29, liposome No. 41, liposome No. 45, liposome No. 53, liposome No. 69, liposome No. 71, liposome No. 76, liposome No. 80, liposome No. 87, liposome No. 91, liposome No. 93, liposome No. 96, liposome No. 105, liposome No. 106, liposome No. 117, liposome No. 125, liposome No. 127, liposome No. 137, liposome No. 139, liposome No. 142, liposome No. 146, liposome No. 150, liposome No. 151, liposome No. 152, liposome No. 153, liposome No. 154, liposome No. 184, liposome No. 186, liposome No. 191, liposome No. 195, liposome No. 199, liposome No. 204, liposome No. 207, liposome No. 213, liposome No. 224, liposome No. 225, liposome No. 229, liposome No. 230, liposome No. 234, liposome No. 235, liposome No. 239, liposome No. 240, liposome No. 263, liposome No. 273, liposome No. 285, and liposome No. 295 shown in Tables 3, 14 and 15. 
   
   
       120 . The delivery vehicle according to  claim 117 , which contains a liposome selected from the group consisting of liposome No. 3, liposome No. 16, liposome No. 27, liposome No. 29, liposome No. 38, liposome No. 40, liposome No. 41, liposome No. 45, liposome No. 50, liposome No. 53, liposome No. 56, liposome No. 60, liposome No. 68, liposome No. 69, liposome No. 70, liposome No. 71, liposome No. 76, liposome No. 80, liposome No. 87, liposome No. 91, liposome No. 93, liposome No. 96, liposome No. 105, liposome No. 106, liposome No. 111, liposome No. 116, liposome No. 117, liposome No. 120, liposome No. 125, liposome No. 127, liposome No. 129, liposome No. 130, liposome No. 137, liposome No. 139, liposome No. 141, liposome No. 142, liposome No. 146, liposome No. 150, liposome No. 151, liposome No. 152, liposome No. 153, liposome No. 154, liposome No. 155, liposome No. 175, liposome No. 178, liposome No. 183, liposome No. 184, liposome No. 186, liposome No. 191, liposome No. 195, liposome No. 197, liposome No. 199, liposome No. 204, liposome No. 207, liposome No. 209, liposome No. 213, liposome No. 218, liposome No. 220, liposome No. 224, liposome No. 225, liposome No. 229, liposome No. 230, liposome No. 233, liposome No. 234, liposome No. 235, liposome No. 236, liposome No. 237, liposome No. 239, liposome No. 240, liposome No. 254, liposome No. 263, liposome No. 273, liposome No. 285, liposome No. 290, liposome No. 292, and liposome No. 295 shown in Tables 3, 14 and 15. 
   
   
       121 . A method for producing a delivery vehicle for achieving the delivery of a desired substance to a desired site, which comprises the steps of:
 A) measuring in vitro affinity of candidate delivery vehicles for a cell surface molecule associated with the desired site; and   B) selecting a delivery vehicle having in vitro affinity corresponding to delivery to the desired site,   in which the cell surface molecule is selected from the group consisting of a lectin, an adhesion molecule, an integrin, an immunoglobulin, a sialomucin, a cadherin, a protein, a lipid, a receptor, an antigen, an enzyme, a metalloprotease, a tyrosine phosphatase, a glycolipid, a glycoprotein, a proteoglycan, a costimuratory molecule, a membrane protein, and an extracellular matrix.   
   
   
       122 . The method according to  claim 121 , which further comprises the step of causing the selected delivery vehicle to contain a substance to be delivered. 
   
   
       123 . The method according to  claim 121 , in which the delivery vehicle contains a sugar-chain-modified liposome. 
   
   
       124 . The method according to  claim 121 , in which the cell surface molecule comprises a lectin selected from the group consisting of (1)C-type lectins such as Hyalectans, Asialoglycoprotein receptors, Collectins (Mannose-binding protein C, Mannose-binding protein A, Pulmonary surfactant protein A, Pulmonary surfactant protein D, Collectin-K1, and Collectin-L1), DC-SIGN, DC-SIGNR, Selectins (E-Selectin, P-Selectin, or L-Selectin), NK group transmembrane receptors, Macrophage mannose receptor, and Single domain lectins; (2) S-type lectins such as galectins (galectin-1, galectin-2, galectin-3, galectin-4, galectin-5, galectin-6, galectin-7, galectin-8, galectin-9, galectin-10, galectin-11, galectin-12, galectin-13, galectin-14, galectin-15, galectin-16, chicken galectin, congerin-1, and congerin-2); (3) I-type lectins such as siglecs (Siglec-1, Siglec-2, Siglec-3, Siglec-4, Siglec-5, Siglec-6, Siglec-7, Siglec-8, Siglec-9, Siglec-10, Siglec-11, Siglec-12, Siglec-12a, Siglec-12b, Siglec-13, Siglec-E, Siglec-F, Siglec-G, or Siglec-H); (4)P-type lectins such as phosphomannosyl receptors; (5) Pentraxins; (6) Calreticulin or calnexin; (7) ERGIC-53 or VIP-36; (8) Discoidins; (9) Fucolectins; (10) Annexin lectins; (11) Ficolins; (12) Tachylectins 5A or 5B; (13) NCAM or Myelin-associated glycoprotein; (14) Amphoterin; (15) CD11b or CD18; (16) CEL-III; (17) Complement factor H; (18) Oxidized LDL receptor; (19) Endosialin; (20) Tachylectin-1 or tachylectin P; (21) Tachylectin-2; (22) Tachylectin-3; (23) Thrombospondin; (24) Interleukin-1; (25) Interleukin-2; (26) Interleukin-3; (27) Interleukin-4; (28) Interleukin-5; (29) Interleukin-6; (30) Interleukin-7; (31) Interleukin-8; (32) Interleukin-12; and (33) Tumor necrosis factor. 
   
   
       125 . The method according to  claim 121 , in which the cell surface molecule contains E-selectin and the site is selected from the group consisting of a site of the liver, a site of the small intestine, a site of the large intestine, a site of the lymph node, a site of the heart, a site of the pancreas, a site of the lungs, a site of the brain, a site of the bone marrow, a site in blood, a site of the kidney, a site of the spleen, a site of the thymus gland, a site of muscle, an inflammation site, and a cancer site. 
   
   
       126 . The method according to  claim 121 , in which the affinity is represented by n % inhibitory concentration (ICn), wherein “n” ranges from 1 to 99. 
   
   
       127 . The method according to  claim 121 , in which the measurement of affinity comprises measurement at a strong binding IC that is approximately IC30 or less and measurement at a weak binding IC that is approximately IC31 or more. 
   
   
       128 . The method according to  claim 121 , in which the measurement of affinity comprises measurement at a strong binding IC that is at least one point between IC30 and IC10 and measurement at a weak binding IC that is at least one point between IC40 and IC60. 
   
   
       129 . The method according to  claim 121 , in which the measurement of affinity comprises measurement at a strong binding IC that is approximately IC30 or less and a candidate having a low inhibitory concentration at the strong binding IC is selected. 
   
   
       130 . The method according to  claim 121 , in which the measurement of affinity comprises measurement at a strong binding IC that is approximately IC30 or less and a candidate having an inhibitory concentration of 10 −9 M or less at the strong binding IC is selected. 
   
   
       131 . The method according to  claim 121 , in which the measurement of affinity comprises measurement at a strong binding IC that is approximately IC30 or less and a candidate having a low inhibitory concentration at the strong binding IC is selected, wherein the selection is performed when at least one condition selected from the group consisting of a condition that the inhibitory concentration at IC 10 is 10 −9 M or less, a condition that an inhibitory concentration at IC20 is 10 −9 M or less and a condition that an inhibitory concentration at IC30 is 10 −9 M or less is satisfied. 
   
   
       132 . The method according to  claim 121 , in which the measurement of affinity comprises measurement at a weak binding IC that is approximately IC31 or more and a candidate having a high inhibitory concentration at the strong binding IC is selected. 
   
   
       133 . The method according to  claim 121 , in which the measurement of affinity comprises measurement at a weak binding IC that is approximately IC31 or more and a candidate having an inhibitory concentration of 10 −9 M or more at the weak binding IC is selected. 
   
   
       134 . The method according to  claim 121 , in which the measurement of affinity comprises measurement at a weak binding IC that is approximately IC31 or more and a candidate having a high inhibitory concentration at the weak binding IC is selected, wherein the selection is performed when at least one condition selected from the group consisting of a condition that the inhibitory concentration at IC40 is 10 −9 M or more, a condition that the inhibitory concentration at IC50 is 10 −9 M or more and a condition that the inhibitory concentration at IC60 is 10 −9 M or more is satisfied. 
   
   
       135 . The method according to  claim 121 , in which the measurement of affinity comprises measurement at a strong binding IC that is approximately IC30 or less and a weak binding IC that is approximately IC31 or more and a candidate having a low inhibitory concentration at the strong binding IC and a high inhibitory concentration at the weak binding IC is selected. 
   
   
       136 . The method according to  claim 121 , in which the measurement of affinity comprises measurement at a strong binding IC that is approximately IC30 or less and a weak binding IC that is approximately IC31 or more and a candidate having an inhibitory concentration of 10 −9 M or less at the strong binding IC and an inhibitory concentration of 10 −9 M or more at the weak binding IC is selected. 
   
   
       137 . The method according to  claim 121 , in which the measurement of affinity comprises measurement at a strong binding IC that is approximately IC30 or less and a weak binding IC that is approximately IC31 or more and a candidate having a low inhibitory concentration at the strong binding IC and a high inhibitory concentration at the weak binding IC is selected,
 wherein the selection is performed when at least one condition selected from the group consisting of a condition that the inhibitory concentration at IC10 is 10 −9 M or less, a condition that an inhibitory concentration at IC20 is 10 −9 M or less and a condition that an inhibitory concentration at IC30 is 10 −9 M or less is satisfied; and in terms of the weak binding IC, at least one condition selected from the group consisting of a condition that the inhibitory concentration at IC40 is 10 −9 M or more, a condition that the inhibitory concentration at IC50 is 10 −9 M or more and a condition that the inhibitory concentration at IC60 is 10 −9 M or more is satisfied.   
   
   
       138 . The method according to  claim 121 , in which the measurement of affinity is performed by a method selected from the group consisting of a competitive inhibition assay, a noncompetitive inhibition assay, and a binding assay. 
   
   
       139 . The method according to  claim 121 , in which the delivery vehicle contains a sugar-chain-modified liposome and the analysis of the composition comprises analysis of the sugar chain type and density of the sugar-chain-modified liposome. 
   
   
       140 . The method according to  claim 121 , in which a linker is used for the modification of liposome. 
   
   
       141 . The method according to  claim 140 , in which the linker is a protein. 
   
   
       142 . The method according to  claim 140 , in which the linker is an albumin. 
   
   
       143 . The method according to  claim 121 , which further comprises a step of hydrophilizing the liposome. 
   
   
       144 . A pharmaceutical composition, which contains a drug to be used for prevention or treatment, and the delivery vehicle according to  claim 112 . 
   
   
       145 . A pharmaceutical composition, which contains a drug to be used for prevention or treatment, and a delivery vehicle that is produced by the method according to  claim 121 . 
   
   
       146 . A method for preventing or treating a subject who requires delivery of a drug to a desired site, which comprises the steps of:
 A) measuring in vitro affinity of candidate delivery vehicles, which are intended for achieving delivery to a desired site, for a cell surface molecule associated with the desired site;   B) selecting a delivery vehicle having in vitro affinity corresponding to delivery to the desired site; and   C) administering a drug required for prevention or treatment to the subject with the use of the selected delivery vehicle,   in which the cell surface molecule is selected from the group consisting of a lectin, an adhesion molecule, an integrin, an immunoglobulin, a sialomucin, a cadherin, a protein, a lipid, a receptor, an antigen, an enzyme, a metalloprotease, a tyrosine phosphatase, a glycolipid, a glycoprotein, a proteoglycan, a costimuratory molecule, a membrane protein, and an extracellular matrix.